In common, complex diseases like asthma, the environment shapes how genotype affects phenotype. An understanding of how the environment, from the cellular to the population level, affects biological responses is critical in broadening our understanding of the genetic risks of disease, and may also help to explain the estimated heritabilities of complex diseases like asthma. In my dissertation, I investigated the genetic and environmental modifiers of immune profiles to gain greater understanding in inter-individual variation in immune response, and how population differences can affect asthma and allergic disease. These studies were completed in two US founder populations of European descent, the Amish and the Hutterites. By comparing the immune profiles of schoolchildren between these two unique populations, we were able to assess the effect of different levels of microbial exposures on asthma prevalence and innate immunity. I also examined the effects of variation on immune response in peripheral blood leukocytes (PBLs) in two separate studies. In the first, I conducted a close investigation of a clinically relevant polymorphism, rs1801274, in FcγIIA receptor on gene expression and cytokine responses to anti-CD3+anti-CD28 antibodies in whole blood and reported a unique response profile in heterozygotes for rs1801274 compared to the major and minor allele homozygotes. Finally, I conducted a quantitative trait loci (QTL) mapping study of cytokine levels in the supernatants of LPS-treated whole blood using a candidate gene approach. Only one association was significant after permutations, suggesting that cytokine QTL studies should be conducted in a more restricted set of cell types.